Ricklis, Rebecca M.

Abstract T is a farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults age ≥ 65 with poor-risk AML, T 600 mg BID for 21 out of 28–63 days induced complete remissions (CR) in 14%, median duration 7.3 mos, median survival 18.3 mos (Lancet JE, et al, Blood109:1387–1394,2007). In vitro, T+E exhibits synergistic anti-AML activity. In an attempt to increase CR rates in elderly AML pts, we conducted a Phase I trial of oral T+E, with escalation of both drugs and 14 vs. 21 days of T every 28–63 days (median 31 days, range 29–50). T+E resulted in a 25% CR rate (21/84 pts), duration 2 – 26+ mos, with best rates achieved with T dose ≥ 400 mg BID for 14 days (Karp JE, et al, Blood108:130a,2006). In the context of this trial, we have conducted longitudinal laboratory studies of changes in DNA damage and apoptosis in AML marrow blasts obtained from 84 patients prior to T+E (Day 0) and on Day 8 of T+E. Blasts were enriched by Ficoll density gradient separation and fixed in 70% ethanol. Persistent, unrepaired DNA damage was quantified by flow cytometry of cells stained with antibody to phosphorylated histone H2AX (γH2AX). Apoptosis was measured by flow cytometry of propidium iodide-stained cells with sub2n DNA content as observed in cell cycle distribution. To date, we have analyzed changes in in vivo γH2AX from 10 pts (4 CR, 6 stable disease or no response, SD/NR). CR pts had a 2-fold increase (range 1.91–2.22) in DNA damage induced by Day 8 of T+E relative to Day 0 values, while patients with SD/NR had no such increase (0–1.06) in DNA damage. Similarly, the apoptotic fraction of the cell cycle distributions of CR patients increase by 2-fold (range 1.2–5.3) for Day 8 marrow blasts. In contrast, changes in apoptosis were widely divergent for SD/NR patients (range 0.2–7.0). Taken together, these preliminary studies on AML marrow blasts obtained prior to and during T+E therapy suggest a possible linkage among induction of DNA damage, apoptotic response, and clinical outcome. Full analysis of all acquired specimens is ongoing.

Abstract The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.